An effect of aging on male reproduction is the progressive decrease in sexual activity from adolescence into old age (Kinsey et al., (1948) Sexual Behavior in the Human Male, W.B. Saunders, Philadelphia, Pa., United States of America). This effect is often attributed to reduced circulating testosterone levels, which occur in all mammalian species studied to date, including humans (Hollander & Hollander, (1958) J. Clin. Endocrinol. 18:966-971; Kirschner & Coffman, (1968) J. Clin. Invest. 47:38-47; Vermeulen (1976) in: Hypothalamus, Pituitary and Aging, (Everitt & Burgess, eds.), Charles C. Thomas, Springfield, Ill., United States of America, pp. 458-463) and rats (Harman et al., (1978) Endocrinol. 102:540-544; Bethea & Walker, (1979) J. Gerontology 34:21-27; Chen et al., (1994) J. Androl. 15:551-557; and Mendis-Handagama & Gelber, (1995) Tissue Cell 27:689-699). Testosterone is necessary in the male reproductive system for many functions, including the regulation of spermatogenesis in the testis, maintenance of the accessory sex organs, and erectile function (Morales et al., (1996) Int. J. Impotence Res. 8:95-97 and Norman & Litwack, (1997) in: Hormones (Norman & Litwack, eds.), Academic Press, San Diego, Calif., United States of America, pp. 169-191).
Testosterone is also required by other organ systems of the mammalian male for their proper functioning. These include, but are not limited to, the brain (for libido and mood), skin (for hair growth and sebaceous gland activity), muscle (to increase muscle strength volume), liver (to synthesize serum proteins), synovial tissue (to modulate immune responses), bone (to maintain strength and volume), bone marrow (to stimulate stem cells), and kidney (to stimulate erythropoietin) (Morales et al., (1996) Int. J. Impotence Res. 8:95-97; Norman & Litwack, (1997) in: Hormones (Norman & Litwack, eds.), Academic Press, San Diego, Calif., United States of America, pp. 169-191; Anderson et al., (1996) Bone 18:171-177; and Gooren, (1996) Br. J. Urol. 78:763-768). Therefore, sustaining the normal levels of circulating testosterone clearly is important for the well being of the male.
Testosterone is primarily produced by the Leydig cells in the testis. Many studies regarding the effects of aging on Leydig cell structure and function have revealed that Leydig cells undergo atrophic changes in size with aging, thus enabling them go into a malfunctioning status (Chen et al., (1994) J. Androl. 15:551-557 and Mendis-Handagama & Gelber, (1995) Tissue Cell 27:689-699) and organelle content (Ichihara et al., (1993) Cell Tissue Res. 271:241-255 and Mori et al., (1982) J. Clin. Endocrinol. Metab. 55:634-641).
A journal article by Valenti et al. attempts to address Leydig cell function (Valenti et al., (1997) International J. Andrology 20(5):279-86). Valenti et al. made adult rats (90 days old) hypothyroidic and examined Leydig cells extracted from the hypothyroidic rats in the presence or absence of several stimuli, notably luteinizing hormone (LH). Thus, Valenti et al. performed in vitro experiments.
A journal article by Maran et al. disclosed a study of the effect of L-3,5,3′-triiodothyronine (T3) on LH-mediated synthesis and secretion of testosterone by Leydig cells in vitro (Maran et al., (2000) Endocr. J. 47:417-28). Maran et al. found that T3 increased testosterone secretion of Leydig cells in a dose dependent fashion up to 50 ng, above which the stimulatory effect was attenuated. Additionally, Maran et al. found that while the minimum effective dose of T3 for testosterone production (25 ng) potentiated the equivalent stimulatory effect of the minimum effective dose of LH (100 ng), 50 ng of T3 attenuated the effect of either LH or T3 dose. Again, the studies of Maran et al. were in vitro. Additionally, the Leydig cells were isolated from young rats: i.e., 60 days old. 60-day-old rats are described as being just at puberal maturation.
Currently, androgen deficiencies in aging humans are treated with androgen therapy (Anderson et al., (1996) Bone 18:171-177 and Gooren, (1996) Br. J. Urol. 78:763-768). The risks of administering androgens to aging men mainly concern the cardiovascular system and the prostate (Gooren, (1996) Br. J. Urol. 78:763-768). Cardiovascular effects of androgens are ascribed to the atherogenic effects of androgens on blood-lipid profiles (Gooren, (1996) Br. J. Urol. 78:763-768). Apart from these effects, androgens can have other possible deleterious metabolic effects on the cardiovascular system. They induce insulin resistance (Polderman et al., (1994) J. Clin. Endocrinol. Metab. 79:275-281) and increased plasma levels of endothelin, a substance with vasoconstrictor properties produced by the vascular wall (Polderman et al., (1993) Ann. Intern. Med. 118:429-432). Regarding the effects of androgens on the prostate, benign prostatic hyperplasia and prostate cancer are the main concerns (Polderman et al., (1993) Ann. Intern. Med. 118:429-432).
In summary, there is a current need in the art for new and improved approaches for enhancing testosterone levels and/or for restoring Leydig cell function in a subject in need thereof. The presently claimed subject matter addresses these and other problems.